Our analysis of gene expression changes during Drosophila aging reveals down- regulation of mitochondrial genes and induction of innate immune response, oxidative stress response, and proteotoxicity response. We will test the hypothesis that sexual differentiation inhibits mitochondrial turnover, and this synergizes with mitochondrial mutations to cause an accumulation of abnormal mitochondria that promote the mitochondrial unfolded protein response (UPRmt), inflammation and aging. We test conserved genes including p53, the dosage compensation (DC) machinery, and dopamine signaling. The methods include florescent transgenic reporter constructs, high-throughput sequencing of mitochondrial genomes and cell transcriptomes, 3D video tracking of fly gene expression and behavior, and testing conserved genes and small molecules for ability to increase life span and reduce inflammation. AIM 1 investigates mechanisms for the trade-off between reproduction and life span, including the DC machinery, p53 and small molecules. AIM 2 addresses mechanisms for cell-specific patterns of aging in oenocytes (liver-like cells), including the UPRmt, MnSOD and mitochondrial mutations. These studies may yield a model system for disease-causing mitochondrial heteroplasmy and mutations in humans. AIM 3 tests possible mechanisms for sex-specific effects of p53 on life span, including autophagy. If successful this research may identify mechanisms for mitochondrial maintenance failure during aging that are (partly) conserved with humans, and may identify promising genetic targets and drugs for sex- specific interventions in human inflammation and aging-related disease.